Title page for ETD etd-06152005-135205


Type of Document Master's Thesis
Author Falwell, Elizabeth Paige
Author's Email Address efalwell@vt.edu
URN etd-06152005-135205
Title Fibrosarcoma-induced Dysregulation of Interleukin (IL)-1β and IL-18 Activities and their Modulation by Paclitaxel
Degree Master of Science
Department Biology
Advisory Committee
Advisor Name Title
Elgert, Klaus D. Committee Chair
Burger, Carol J. Committee Member
Gogal, Robert M. Jr. Committee Member
Keywords
  • paclitaxel
  • IL-12
  • fibrosarcoma
  • IL-1β
  • NF-κB
  • nitric oxide
  • IL-18
Date of Defense 2005-06-07
Availability unrestricted
Abstract
Cancer remains an elusive killer due, in part, to the suppression of normal immunologic antitumor responses. Normal host (NH) macrophage (Mφ) populations have tumoricidal effects such as tumor antigen phagocytosis and presentation, and cytokine production. Tumor-infiltrating Mfs may evade these activities by dysregulating production of immunostimulatory cytokines (including Interleukin [IL]-1β, IL-18, and tumor necrosis factor-α [TNF-α]), by production of antagonistic factors. The restoration of IL-1β,

IL-18, and TNF-α production by Mφs could re-establish antitumor host immune

responses. Previous work in our laboratory suggests that tumor distal (TD) Mφs produce

more IL-1β than NH Mφs when stimulated with IFN-γ and lipopolysaccharide (LPS). We

hypothesize that the presence of immunomodulatory factors like IL-10 and TGF-β

dysregulate IL-1β production in tumor proximal (TP) Mφs. Indeed, IL-1β production was

downregulated among in situ TP Mφs. We have proposed that IL-18, a structural

homologue to IL-1β was similarly dysregulated in TD and TP Mφs. IL-18 was enhanced

in both distal and proximal Mφs. Differences in the functions of these cytokines could

account for this dissimilarity. TNF-α, another proinflammatory cytokine, followed the

dysregulation pattern of IL-1β in our tumor-burdened hosts (TBH), likely because of the

similar functions of these cytokines. Because it is a potential vehicle for

immunotherapeutic treatment, paclitaxel’s action on the immune response (TAXOL™)

was investigated. Paclitaxel is a potent Mφ activator that upregulates a variety of

cytokines in an LPS-like manner. Paclitaxel enhanced TD Mφ production of IL-1β, IL-18,

and TNF-α in an LPS-like manner. Production of IL-1β and TNF-α was reduced in TP

Mφs when treated with paclitaxel; however, IL-18 production was enhanced. This

difference could be due to the different functions of IL-1β and IL-18. To determine

whether production of these cytokines translates into downstream expression of

transcription products, IL-12 and nitric oxide (NO) were assayed. NO was enhanced

distally, but paclitaxel treatment failed to enhance NO production. When treated with

paclitaxel, IL-12 was produced by NH and TD Mφs. Collectively, these studies suggest

that tumor-induced cytokine imbalances compromise antitumor immunity and paclitaxel

may reverse this activity.

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